In addition, HBCs in culture have a demonstrated capacity to generate neurons, as well as nonneuronal cells (Carter et al., 2004). Finally, cre-lox lineage tracing studies have firmly established that HBCs can give rise in vivo to all cells of the olfactory epithelium—including the GBCs—under conditions of normal turnover, as well as injury-induced regeneration (Iwai et al., 2008 and Leung et al., 2007). In one model that reconciles these two views, the GBCs are find more a heterogeneous

class (comprising both neuronally committed and multipotent progenitors) that supports normal turnover in the olfactory epithelium, whereas the HBCs represent a reserve stem cell pool that divides infrequently to replace GBCs, which are slowly depleted over the lifetime of the animal (Duggan and Ngai, 2007 and Leung et al., 2007). HBCs are stimulated to proliferate more actively during injury-induced regeneration to replace the GBCs and eventually all of the mature cell types of the epithelium (Figure 1A). Indeed, in other regenerating

Cisplatin cost systems, there is a precedent for such a reserve stem cell pool. For example, the slowly dividing bulge epithelial stem cells of the hair follicle replenish more actively proliferating progenitors and are stimulated to proliferate in response to injury (Fuchs, 2009 and Li and Clevers, 2010). What are the transcriptional networks governing self-renewal and differentiation of the adult tissue stem cell of the olfactory epithelium? To address this issue, we performed whole-genome transcriptome profiling on quiescent HBCs purified by fluorescence-activated cell sorting (FACS) as a means of identifying transcripts enriched in these cells. Through this analysis, we found that the mRNA encoding the transcription factor p63 is among the most highly enriched transcripts in these cells, a finding that was validated by RNA in situ hybridization and immunohistochemistry. p63 is a member of the p53 tumor suppressor gene

family that is expressed by stem cells in a variety of stratified epithelia (Osada et al., 1998 and Yang et al., first 1998). p63 gene knockouts in the mouse have demonstrated its role as a key regulator of ectoderm- and endoderm-derived epithelial stem cells, where it functions to maintain their self-renewing proliferative capacity and/or cell survival ( Mills et al., 1999, Senoo et al., 2007, Su et al., 2009a, Su et al., 2009b, Truong et al., 2006 and Yang et al., 1999). Other studies have implicated p63 in promoting epithelial differentiation events ( Candi et al., 2006a, Candi et al., 2006b, Koster et al., 2004, Koster et al., 2007 and Truong et al., 2006), although this aspect of p63 function remains controversial ( Blanpain and Fuchs, 2007 and Crum and McKeon, 2010). A recent analysis of newborn pups harboring a germline p63 null mutation demonstrated that p63 is required for the generation of HBCs from progenitor cells during late embryogenesis ( Packard et al.